Pain is a well known phenomenon as an indicator of injury or tissue damage due to inflammation, ischemia, mechanical or other irritation [Juan, H., Prostaglandins as Mediators of Pain, Gen. Pharmacy, 9.403-409 (1978)].
The first step leading to the sensation of pain is the activation of nociceptive primary afferents by intense thermal, mechanical or chemical stimuli. Indirect studies of nociceptive transduction (activation) indicate that it involves chemical mediators that are released or synthesized in response to tissue damage [Fields, H. and Levine, J., Pain-Mechanisms and Management, Western Medical J. 141,347-357 (1984)]. These chemical mediators include lactic acid, hypertonic saline, histamine, 5-hydroxytryptamine, potassium chloride, acetylcholine, purines, bradykinin and substance P which are referred to as algesic agents (Juan, H., Supra). In recent years it has been shown that prostaglandins and leukotrines can contribute to the activation of primary afferent nociceptors (Fields, H. and Levine, J., Supra). Prostaglandins are uniquely distinguished from the other chemical mediators in that they induce a state of hyperalgesia by elevating the sensitivity of pain receptors to other painful or algasic stimuli.
The stimulation of primary afferents leads to action potentials in their axons which propagate to the spinal cord. In addition, excited primary afferents release nuropeptides (substance P, calciotonin-gene-related peptide, neurokinin A) at their peripheral terminals. Neuropeptides enhance inflammatory reactions in the injured tissue, contributing to vasodilation, edema, and increased vascular permeability; this phenomenon is called `neurogenic inflammation`.
In the spinal cord, the nociceptors enter the gray matter of the superficial dorsal horn to synapse on nerve cells contributing to pain-transmission pathways such as the spinothalamic and spinoreticulothalamic tracts which terminate in two separate regions in the thalamus. The two thalamic regions in turn project to different cortical sites (Fields, J. and Levina, J., Supra).
The pain transmitting and modulating system depicted so far depends on numerous chemical moieties for its integrated function [Fine, P. and Hare, B., The Pathways and Mechanisms of Pain and Analgesis, L A Review and Clinical Perspective, Hospital Formul. 20, 972-985 (1985)].
Anesthetics block neuronal transmission and affect sensation as well as pain. Analgesics act by interfering with the activity of chemical mediators without affecting sensory input.
According to Remington's Pharmaceutical Sciences, 17th Ed., analgesics can be classified as falling into at least three loose groups: 1) the opiate-based (narcotic) analgesics; 2) the non-opiate analgesics; and 3) analgesics and antipyretics.
The opiate-based analgesics include opium derived alkaloids, including morphine, codeine, and their various derivatives, opiate antagonists, the several morphine derivatives which have morphine antagonist activity, but have analgesic activity.
Since these narcotic type drugs are addictive, a number of nonaddictive, non-opiate analgesics have been developed in an attempt to produce an analgesic which is highly efficient but not addictive.
In the third broad category, the analgesics and antipyretics, are the salicylates and acetamide-containing compounds and the so-called non-steroidal anti-inflammatory drugs. They are non-addictive pain killers.
As to their mode of action, drugs that block perception of pain may be said to act either centrally (such as narcotics) or peripherally.
Centrally acting narcotic drugs are true analgesics because they can relieve pain regardless of the etiology.
The non-steroidal anti-inflammatory agents (NSAIAs) have been described as peripheral pain relievers. It was further suggested that the analgesic properties of these drugs are independent of their antiedema or anti-inflammatory actions [Capetola et al., Supra].
The action of NSAIAs as pain relievers is associated with the biosynthesis of prostanoids.
Inflammation or trauma and resultant tissue injuries cause the release of arachidonic acid which is degraded by cyclo-oxygenase and lipoxygenase. The cyclo-oxygenase pathway leads to the synthesis of prostaglandin E.sub.2 (PGE.sub.2) and other mediators. PGE.sub.2 release increases the cyclic AMP and ionic calcium levels at the nociceptor membrane resulting in a lowered activation threshold, resulting in the relay to the central nervous system of augmented pain perception (hyperalgesia) [Capetola et al., Peripheral Antialgesics: A Review, J. Clin. Pharmacol. 23, 545-556 (1983)]. Inhibitors of prostaglandin synthesis, such as NSAIAs, act avoiding the sensitizing effects of prostaglandins on nociceptive endings and therefore, the decrease in pain threshold.
In animal models and human studies non-steroidal antiinflammatory agents have been shown to inhibit inflammatory pain [Terasawa et al., Analgesic effect of topically applied pranoprofen-gel, Nippon Yakurigaku Zasshi 86(6), 433-440 (1985); Cherevatov et al., Topical Use of Rheumon-Gel in combined treatment of patients with rheumatoid arthritis, Ter. Arkh. (USSR), 59(12) 100-102 (1987); and Kyuki et al., Anti-inflammatory Effect of diclofenac-sodium ointment (cream) in topical application, Jpn. K. Pharmacol, 33(1), 121-123 (February 1983)].
Ophthalmic applications of various NSAIAs are also known, including the utilization of their anti-inflammatory properties for control of various ocular inflammations. [See Anderson et al., Disposition of topical flurbiprofen in normal and aphakic rabbit eyes, Arch. Ophthalmol, 100, 642-645 (1982); Duffin et al., Inhibitors of surgically induced miosis, Ophthalmol, 86, 966-979 (1983); and Keates and McGowan, Clinical trial of flurbiprofen to maintain pupillary dilation during cataract surgery, Ann. Ophthalmol, 16(10), 919-921 (1984).
NSAIAs have been used for the treatment of non-inflammatory, localized pain, such as non-inflammatory ocular pain. See U.S. patent application Ser. No. 07/585,664, filed on Sep. 20, 1990 in the of Gwon.
Calcium channel blockers or antagonists are compounds which delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under ischaemic conditions. Calcium overload, during ischaemia, can have a number of additional adverse effects which would further compromise the ischaemic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly, promotion of cell necrosis. Thus, the compounds are useful in the treatment or prevention of cardiac conditions, such as angina pectoris, cardiac arrhythmias, heart attacks and cardiac hypertrophy. The compounds also possess vasodilator activity and are thus useful as antihypertensives and for the treatment of coronary vasospasm. Calcium channel blockers of the verapamil type are known to lower elevated intraocular pressure. See U.S. Pat. No. 4,981,871. Calcium channel blockers are not suggested as useful for treating pain, including ocular pain.